Venous ThromboembolismPhase 4COBRRANCT03266783
Comparison of Bleeding Risk Between Rivaroxaban and Apixaban for the Treatment of Acute Venous Thromboembolism
A Phase 4 study testing Apixaban and Rivaroxaban in people with Venous Thromboembolism, run by Ottawa Hospital Research Institute at 19 sites in 3 countries.
Trial summary
Apixaban and rivaroxaban have been compared to standard therapy for treatment of acute symptomatic venous thromboembolism (VTE) in randomized controlled trials (RCTs), and are both approved by Health Canada. No safety or efficacy data is available from direct head-to-head comparison of these two anticoagulants. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Venous Thromboembolism
- What is being tested?
- Apixaban and Rivaroxaban
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2,760 participants
- Where
- 19 sitesin 3 countries
- Study dates
- 13 Dec 2017to 15 Oct 2025
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Confirmed newly diagnosed symptomatic acute venous thromboembolism (VTE) [proximal lower extremity deep vein thrombosis (DVT) or segmental or greater pulmonary embolism (PE)]
- Age ≥ 18 years old
- Informed consent obtained
Who cannot join
- Have received > 72 hours of therapeutic anticoagulation
- Creatinine clearance < 30 ml/min calculated with the Cockcroft-Gault formula
- Any contraindication for anticoagulation with apixaban or rivaroxaban as determined by the treating physician such as, but not limited to:
- active bleeding,
- active malignancy, defined as a) diagnosed with cancer within the past 6 months; or b) recurrent, regionally advanced or metastatic disease; or c) currently receiving treatment or have received any treatment for cancer during the 6 months prior to randomization; or d) a hematologic malignancy not in complete remission,
- weight > 120 kg,
Show all 10Show fewer
- liver disease (Child-Pugh Class B or C),
- use of contraindicated medications
- another indication for long-term anticoagulation (e.g. atrial fibrillation)
- pregnant (note below) or breastfeeding (Note: as reported by the patient or a pregnancy test will be ordered at the discretion of the treating physician for women of childbearing potential as per standard of care)
Trial locations and contacts
19 sites in 3 countries.
19 sites in 3 countries
Canada17 sites
University of Calgary
Calgary, Alberta
Alberta Health Sciences
Edmonton, Alberta
QEII Health Science Centre
Halifax, Nova Scotia, B3H 2Y9
Hamilton General Hospital
Hamilton, Ontario
Juravinski Hospital
Hamilton, Ontario
St. Joseph's Healthcare Hamilton
Hamilton, Ontario
Kingston General Hospital
Kingston, Ontario
London Health Sciences Center
London, Ontario, N6A 5W9
Jewish General Hospital
Montreal, Quebec, H3T 1E2
McGill University Health Center
Montreal, Quebec, H4A 3J1
Hôpital Sacré-Coeur de Montréal
Montreal, Quebec
St. Mary's Hospital
Montreal, Quebec
The Ottawa Hospital - General Campus
Ottawa, Ontario, K1H 8L6
CHU de Québec-Université Laval
Québec, Quebec
University of Sherbrooke
Sherbrooke, Quebec
UHN - Toronto General Hospital
Toronto, Ontario, M5G 2C4
St. Paul's Hospital
Vancouver, British Columbia
Australia1 site
The University of Sydney
Darlington, New South Wales, 200606
Ireland1 site
The Royal College of Surgeons in Ireland/Mater Misericordiae University Hospital
Dublin
About this study
Apixaban and rivaroxaban have been compared to standard therapy for treatment of acute symptomatic venous thromboembolism (VTE) in randomized controlled trials (RCTs), and are both approved by Health Canada. No safety or efficacy data is available from direct head-to-head comparison of these two anticoagulants. Lawsuits in the United States over bleeding events, patient perceptions, and concerns with medication adherence are additional factors highlighting the importance of a comparison trial. This multi-center, pragmatic, prospective, randomized, open-label, blinded end-point (PROBE) trial aims to compare the safety of apixaban and rivaroxaban for the treatment of VTE.
Read the detailed description
VTE is the third leading cause of mortality by cardiovascular disease. Standard treatment for acute VTE uses a combination of parenteral Low-Molecular-Weight Heparin (LMWH) and oral vitamin K antagonists (VKA) for 3 months, and carries significant bleeding risk. The major and/or clinically-relevant non-major bleeding (CRNMB) event rate is reported between 8.1-9.7% during initial treatment. This treatment is burdensome owing to subcutaneous injections, drug interactions, and laboratory monitoring. Direct oral anticoagulants (DOACs) are simpler to use and do not require laboratory monitoring.
Rivaroxaban and apixaban are two DOACs targeting Factor Xa. Each DOAC was separately proven effective and safe when compared to standard treatment. Comparison of the bleeding rates between studies would favour use of apixaban over rivaroxaban; however, trial limitations and lack of direct comparison between these two agents makes it impossible to draw firm conclusions. This represents a dilemma in clinical practice because the absence of convincing differences in safety has led to genuine uncertainty about which DOAC has the best risk-to-benefit ratio.
To address these limitations, a head-to-head randomized controlled trial (RCT) is needed to determine the safety (i.e. bleeding risk) of twice daily apixaban over once daily rivaroxaban during the first 3 months of acute VTE treatment. Eligibility criteria will be less stringent than the COBRRA pilot study and reflect real-world patients. Cost-effective analysis of apixaban twice daily compared to rivaroxaban once daily will also be performed.
- Conditions
- Venous Thromboembolism
- Being tested
- Apixaban, Rivaroxaban
- Medical subject headings
- Venous Thromboembolism
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ApixabanDrug
Also called Eliquis
Refer to Apixaban group
RivaroxabanDrug
Also called Xarelto
Refer to Rivaroxaban group
| Study group | Role | What they receive |
|---|---|---|
| Apixaban group | Active comparator | 10 mg orally (PO), twice a day (BID) for 1 week, then 5 mg PO BID for 3 months of treatment Receives: Drug: Apixaban |
| Rivaroxaban group | Active comparator | 15 mg orally (PO), twice a day (BID) for 3 weeks, then 20 mg PO once a day (OD) for 3 months of treatment Receives: Drug: Rivaroxaban |
What is being measured
The primary outcome is the main question the study is designed to answer.
The Rate of Adjudicated Clinically Relevant Bleeding (CRB) Events
CRB events are defined as the composite of major bleeding (MB) events and clinically relevant non-major bleeding (CRNMB) events.
Measured: For the duration of the study: 3 months
Secondary outcomes (9)
Number of Participants With Adjudicated Major Bleeding Events
Major bleeding will be defined as fatal bleeding, and/or, Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or bleeding causing a fall in hemoglobin of ≥20 g/L, or leading to transfusion of ≥2 units of whole blood or red cells.
Measured: For the duration of the study: 3 months
Number of Participants With Adjudicated Clinically Relevant Non-Major Bleeding Events
Clinically relevant non-major bleeding will be defined as any sign or symptom of hemorrhage (e.g., more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for the International Society on Thrombosis and Haemostasis (ISTH) definition of major bleeding but does meet at least one of the following criteria:
- Requiring medical intervention by a healthcare professional
- Leading to hospitalization or increased level of care
- Prompting a face to face (i.e., not just a telephone or electronic communication) evaluation
Measured: For the duration of the study: 3 months
Number of Participants With Adjudicated Recurrent Venous Thromboembolism (VTE) Events
Recurrent VTE will be confirmed with investigational reports including clinic notes, D-dimer results and imaging as per standard of care. Recurrent Deep Vein Thrombosis (DVT) will be confirmed by compression ultrasound revealing a new (compared to baseline/index ultrasound) area of non-compressibility in the popliteal vein or more proximal vein, or venography demonstrating a constant intraluminal filling defect in the popliteal vein or more proximal veins. Recurrent Pulmonary Embolism (PE) will be diagnosed if the Ventilation-Perfusion (VQ) scan is non-normal and a new unmatched segmental or greater perfusion defect is documented, or an intraluminal filling defect is seen on Computed Tomography Pulmonary Angiogram (CTPA) in a segmental or greater vessel that was previously free of thrombus, or pulmonary angiography demonstrating a constant intraluminal filling defect or a cutoff of a vessel >2.5 mm in diameter will be considered diagnostic for PE.
Measured: For the duration of the study: 3 months
Number of Participants With Adjudicated VTE-Related Deaths
VTE-related death (fatal PE or unexplained deaths) will be confirmed using death certificates and/or autopsy findings.
Measured: For the duration of the study: 3 months
All-cause Mortality
Using a binary outcome of an event or no event (Individual rates of death related to VTE, bleeding or other causes).
Measured: For the duration of the study: 3 months
Medication Adherence
Reported as the number of patients self-reporting full medication adherence.
Measured: For the duration of the study: 3 months
Quality-Adjusted Life Years (QALYs) Gained
We will measure health utility values using the EQ-5D-5L (EuroQoL-5 Dimension-5 Level) Questionnaire at baseline, 2 week (± 7 days), and 90 days (+14 days). We will model the prognosis of a cohort of patients receiving rivaroxaban as a baseline against the potential impact of apixaban. The results will be presented as incremental cost per QALY gained, incremental costs per one CRB cases prevented, and incremental cost per one life year saved.
Measured: For the duration of the study: 3 months
Incremental Cost-effectiveness Ratio
Incremental cost-effectiveness ratios including cost per one CRB case prevented, cost per one life year saved, cost per one quality-adjusted life year (QALY) gained, which will be analyzed as part of the health economic analysis plan.
Measured: For the duration of the study: 3 months
Impact of Verbal Consent on Patient Participation in Comparison With Participants From Sites Using Written Informed Consent
Impact of verbal consent on patient participation in comparison with participants from sites using written informed consent. Due to the qualitative nature of this outcome, it will be presented descriptively.
Measured: For the duration of the study: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Aug 2017
- Study start13 Dec 2017
- Primary completion30 Apr 2025
- Study completion15 Oct 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Venous ThromboembolismStudies of the same condition, open and under way.
- More trials run by Ottawa Hospital Research InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 2,760 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ottawa Hospital Research Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network, Canadian Institutes of Health Research (CIHR)
- Responsible party
- Sponsor
- Investigators
- Lana Castellucci, MD, FRCPC, Principal investigator, Ottawa Hospital Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03266783
- Sponsor's protocol ID
- COBRRA
- Acronym
- COBRRA
- Status last verified
- May 2026
- First submitted
- 10 Aug 2017
- Last updated
- 24 Jun 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Castellucci LA, Chen VM, Kovacs MJ, Lazo-Langner A, Greenstreet P, Kahn S, Cote B, Schulman S, de Wit K, Douketis J, Suryanarayan D, Wan T, Yeo E, Le Templier G, Tran HA, Willcox A, Crowther HJ, Prasad R, Shivakumar S, Umana E, Ni Ainle F, Tritschler T, Barco S, Galanaud JP, Blondon M, Baumann Kreuziger L, Solymoss S, Kearon C, Thomas E, Ramsay T, Le Gal G, Rodger M; COBRRA Trial Investigators. Bleeding Risk with Apixaban vs. Rivaroxaban in Acute Venous Thromboembolism. N Engl J Med. 2026 Mar 12;394(11):1051-1060. doi: 10.1056/NEJMoa2510703.
PubMed 41812192
Study at a glance
From the registry record, last updated by the sponsor on 24 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparison of Bleeding Risk Between Rivaroxaban and Apixaban for the Treatment of Acute Venous Thromboembolism
- ClinicalTrials.gov ID
- NCT03266783
- Acronym / sponsor ID
- COBRRA / COBRRA
- Conditions
- Venous Thromboembolism
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 2,760 participants (actual)
- Lead sponsor
- Ottawa Hospital Research InstituteUniversity, hospital or other
- Collaborators
- Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network, Canadian Institutes of Health Research (CIHR)
- Study start
- 13 Dec 2017 (actual)
- Primary completion
- 30 Apr 2025 (actual)
- Study completion
- 15 Oct 2025 (actual)
- First posted
- 30 Aug 2017 (actual)
- Results
- Posted 24 Jun 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Apixaban and rivaroxaban have been compared to standard therapy for treatment of acute symptomatic venous thromboembolism (VTE) in randomized controlled trials (RCTs), and are both approved by Health Canada. No safety or efficacy data is available from direct head-to-head comparison of these two anticoagulants. Lawsuits in the United States over bleeding events, patient perceptions, and concerns with medication adherence are additional factors highlighting the importance of a comparison trial. This multi-center, pragmatic, prospective, randomized, open-label, blinded end-point (PROBE) trial aims to compare the safety of apixaban and rivaroxaban for the treatment of VTE.
Detailed description
VTE is the third leading cause of mortality by cardiovascular disease. Standard treatment for acute VTE uses a combination of parenteral Low-Molecular-Weight Heparin (LMWH) and oral vitamin K antagonists (VKA) for 3 months, and carries significant bleeding risk. The major and/or clinically-relevant non-major bleeding (CRNMB) event rate is reported between 8.1-9.7% during initial treatment. This treatment is burdensome owing to subcutaneous injections, drug interactions, and laboratory monitoring. Direct oral anticoagulants (DOACs) are simpler to use and do not require laboratory monitoring.
Rivaroxaban and apixaban are two DOACs targeting Factor Xa. Each DOAC was separately proven effective and safe when compared to standard treatment. Comparison of the bleeding rates between studies would favour use of apixaban over rivaroxaban; however, trial limitations and lack of direct comparison between these two agents makes it impossible to draw firm conclusions. This represents a dilemma in clinical practice because the absence of convincing differences in safety has led to genuine uncertainty about which DOAC has the best risk-to-benefit ratio.
To address these limitations, a head-to-head randomized controlled trial (RCT) is needed to determine the safety (i.e. bleeding risk) of twice daily apixaban over once daily rivaroxaban during the first 3 months of acute VTE treatment. Eligibility criteria will be less stringent than the COBRRA pilot study and reflect real-world patients. Cost-effective analysis of apixaban twice daily compared to rivaroxaban once daily will also be performed.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Apixaban group | Active comparator | Drug: Apixaban10 mg orally (PO), twice a day (BID) for 1 week, then 5 mg PO BID for 3 months of treatment |
| Rivaroxaban group | Active comparator | Drug: Rivaroxaban15 mg orally (PO), twice a day (BID) for 3 weeks, then 20 mg PO once a day (OD) for 3 months of treatment |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Confirmed newly diagnosed symptomatic acute venous thromboembolism (VTE) [proximal lower extremity deep vein thrombosis (DVT) or segmental or greater pulmonary embolism (PE)]
- Age ≥ 18 years old
- Informed consent obtained
Key exclusion criteria (10 listed)
- Have received > 72 hours of therapeutic anticoagulation
- Creatinine clearance < 30 ml/min calculated with the Cockcroft-Gault formula
- Any contraindication for anticoagulation with apixaban or rivaroxaban as determined by the treating physician such as, but not limited to:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ApixabanAlso: EliquisRefer to Apixaban group | Drug | Apixaban group |
| RivaroxabanAlso: XareltoRefer to Rivaroxaban group | Drug | Rivaroxaban group |
Primary outcome
The Rate of Adjudicated Clinically Relevant Bleeding (CRB) Events
Time frame: For the duration of the study: 3 months
CRB events are defined as the composite of major bleeding (MB) events and clinically relevant non-major bleeding (CRNMB) events.
9 secondary outcomes
Number of Participants With Adjudicated Major Bleeding Events
Time frame: For the duration of the study: 3 months
Number of Participants With Adjudicated Clinically Relevant Non-Major Bleeding Events
Time frame: For the duration of the study: 3 months
Number of Participants With Adjudicated Recurrent Venous Thromboembolism (VTE) Events
Time frame: For the duration of the study: 3 months
Number of Participants With Adjudicated VTE-Related Deaths
Time frame: For the duration of the study: 3 months
All-cause Mortality
Time frame: For the duration of the study: 3 months
Medication Adherence
Time frame: For the duration of the study: 3 months
Quality-Adjusted Life Years (QALYs) Gained
Time frame: For the duration of the study: 3 months
Incremental Cost-effectiveness Ratio
Time frame: For the duration of the study: 3 months
Impact of Verbal Consent on Patient Participation in Comparison With Participants From Sites Using Written Informed Consent
Time frame: For the duration of the study: 3 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Jun 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41812192Castellucci LA, Chen VM, Kovacs MJ, Lazo-Langner A, Greenstreet P, Kahn S, Cote B, Schulman S, de Wit K, Douketis J, Suryanarayan D, Wan T, Yeo E, Le Templier G, Tran HA, Willcox A, Crowther HJ, Prasad R, Shivakumar S, Umana E, Ni Ainle F, Tritschler T, Barco S, Galanaud JP, Blondon M, Baumann Kreuziger L, Solymoss S, Kearon C, Thomas E, Ramsay T, Le Gal G, Rodger M; COBRRA Trial Investigators. Bleeding Risk with Apixaban vs. Rivaroxaban in Acute Venous Thromboembolism. N Engl J Med. 2026 Mar 12;394(11):1051-1060. doi: 10.1056/NEJMoa2510703.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lana Castellucci, MD, FRCPC principal investigator
Ottawa Hospital Research Institute
19 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Apixaban and Rivaroxaban in people with Venous Thromboembolism, run by Ottawa Hospital Research Institute at 19 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in Canada, Australia, Ireland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Jun 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The Rate of Adjudicated Clinically Relevant Bleeding (CRB) Events (time frame: For the duration of the study: 3 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03266783, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jun 2026.